1. Field of the Invention
The invention relates to method of enhancing gonadal development in an animal by administration of an agent which results in lowered levels of a thyroid hormone such as T3 and elevation of plasma gonadotropins (luteinizing hormone (LH) and follicle stimulating hormone (FSH)).
2. Related Art
Over the past few decades two environmental manipulations have been used in the poultry industry to regulate the onset of sexual maturation: photoperiod and nutrition. Pullets kept in total darkness or under short photoperiods display a delay in initial egg production (Wilson and Woodward, Poultry Sci. 37:1054-1057 (1958); King, Poultry Sci. 40:479-484 (1961)). In contrast, increasing day lengths have been shown to stimulate reproductive development in many avian species including domestic fowl (Farner and Follett, J. Anim. Sci. 25:Suppl. 90-118 (1966); van Tienhoven and Planck, The effect of light on avian reproductive activity, Handbook of Physiology, Endocrinology II, Part 1, Chapter 4, pp. 79-107 1972). Chicks can be maintained at a physiological age of about 10 days for many months using protein-, amino acid-, or energy-deficient diets just sufficient to fill maintenance requirements (McCance, Br. J. Nutr. 14:59-73 (1960); Dickerson and McCance, Br. J. Nutr. 14:331-338 (1960)). Return to an unrestricted, nutritional diet restores growth and development to a normal rate with little subsequent effect on adult body size or egg production (McRoberts, J. Nutr. 87:31-40 (1965)).
Continued manipulation of photoperiod and nutrition (particularly feed restriction) has been used in the broiler industry. The latter has become a necessary management tool due to a propensity for broiler-breeders to become obese. This is a consequence of the marked improvements in weight gain and feed conversion made by genetic selection and advances in the knowledge of dietary requirements. Unfortunately, rapid growth rate in broilers has resulted in obesity and decreased efficiency in the reproductive system of breeder stock (Reddy, Artificial insemination of broilers: economic and management implications. In:Proceedings of the First International Symposium on the Artificial Insemination of Poultry. The Poultry Science Assoc., Inc., Savoy, Ill., pp.73-89, 1994). Research has been completed comparing the reproductive performance of females between broiler breeder and egg-laying strains of domestic chickens (Dunn and Sharp, J. Reprod. Fert. 90:329-335 (1990); Eitan and Soller, Poultry Sci. 70:2017-2022 (1991); Poultry Sci. 73:769-780 (1994); Poultry Sci. 75:828-832 (1996); Robinson, Ovarian form and function in chickens of varying reproductive status. Final Report, Alberta Agricultural Research Institute Project # AAR1920202. Univ. Alberta, Edmonton, Canada (1994); Eitan et al. Poultry Sci. 77:1593-1600 (1998)). Conclusions that have been reached from the cited studies are:
1. Female broilers compared to Leghorns are less responsive to photoperiodic manipulations with respect to optimal reproductive performance (Eitan and Soller, Poultry Sci. 70:2017-2022 (1991); Poultry Sci. 73:769-780 (1994); Eitan et. al. Poultry Sci. 77:1593-1600 (1998));
2. Layer and broiler females differ in the minimal number of hours of light required to stimulate release of gonadotropins and initial development of their reproductive systems [critical day length, (CDL)] and the minimal number of hours of light above which no further increase in release of gonadotropins occurs [saturation day length, (SDL)] (Dunn and Sharp, J. Reprod. Fert. 90:329-335 (1990); Eitan et al. Poultry Sci. 77:1593-1600 (1998)); and,
3. Broiler breeder hens are less responsive to artificially increased photoperiodic manipulations compared to table egg layers under the effects of feed restriction (Robinson, Ovarian form and function in chickens of varying reproductive status. Final Report, Alberta Agricultural Research Institute Project # AAR1920202. Univ. Alberta, Edmonton, Canada (1994); Eitan et al. Poultry Sci. 77:1593-1600 (1998)).
Eitan and Soller, Poultry Sci. 75:828-832 (1996), compared the performance of male broiler breeders to that of male Leghorn or layer-type poultry under controlled photoperiod and/or dietary manipulations. They developed a maturation index for comparing different lines of birds.
There are clear indications that the reproductive system of broiler breeders has been compromised, particularly during the past decade (Beaumont, et al. Br. Poult. Sci. 33:649-661 (1992); Reddy, Artificial insemination of broilers: economic and management implications. In:Proceedings of the First International Symposium on the Artificial Insemination of Poultry. The Poultry Science Assoc., Inc., Savoy, Ill., pp.73-89 (1994); Eitan and Soller, Poultry Sci. 75:828-832 (1996); Goerzen et al. Poultry Sci. 75:962-965 (1996)). Elite male broiler breeders have been shown to exhibit premature loss of adequate numbers of viable spermatozoa. It has been suggested that up to 80% of selected males in pure lines are lost due to significant decreases in semen production (Personal communication with primary breeder personnel in the broiler industry; unpublished data from over 200 male broiler breeders). This marked reduction of selection potential can dramatically reduce genetic progress that can be made within a given type of bird, reducing the future competitiveness of specific lines.
Sulfamethazine (SMZ) is an antibiotic developed by Merck in the late 1940s for treating fowl cholera (Kiser et al. Poultry Sci. 27:257-262 (1948)) as well as other poultry diseases, such as coccidiosis. A side effect associated with chronic use of SMZ is a marked red coloration of the comb and increased size of both comb and testes (van Tienhoven et al. Poultry Sci. 35:179-191 (1956)). Its mechanism of action in this regard is unknown. Further studies have been conducted with broiler chicks. The compound significantly increases testes development, transiently suppresses a thyroid hormone, increases plasma gonadotropins, appears to augment photoperiodic response, induces the hypothalamo-pituitary-gonadal axis, and increases the number of immuno-stained neuropeptide Y(NPY) neurons in the mediobasal hypothalamus and infundibular nucleus (IN) (Macko, Walsh and Kuenzel, Brain Res. Bull. 44:707-713 (1997); Kuenzel, Macko, Walsh and Proudman, In Perspectives in Avian Endocrinology (Eds. S. Harvey and R. J. Etches), Journal Endocrinology Ltd., Bristol, pages 81-90 (1997). In addition, it has been shown that intracerebroventricular (ICV) administration of NPY to chicks stimulates growth of the testes (Fraley and Kuenzel, Life Sci. 52:1649-1656 (1993)). In the rat, it has been shown that NPY neurons in the arcuate nucleus [the IN of the chick is equivalent to the arcuate n. (ARC) of mammals, (Kuenzel and van Tienhoven, J. Comp. Neurol. 206:292-313 (1982)), appear to be involved in augmenting the LH surge in females (Kaira and Crowley, Ann. N.Y. Acad. Sci. 611:273-283 (1984); Sar et al. Endocrinology 127:2752-2756 (1990)).
The invention relates to a method for enhancing the development of viable sperm in a male animal and ovarian development in a female animal, comprising administering to said animal an effective amount of an agent which transiently lowers the levels of a thyroid hormone, specifically T3, e.g. by affecting its synthesis or metabolism, and which agent also increases gonadotropins. The most robust effect occurs in males. Normally, semen is not obtained from commercial poultry lines until 16-25 weeks of age. According to the present invention, semen production is produced by 9 weeks of age. Thus, the present invention represents a significant advance in the art.
The invention also relates to a method for synchronizing the onset of puberty in feed-restricted and light-restricted birds by administering to the birds the agent on or about the time that the photoperiod is increased (e.g. weeks 20 through 28 for broiler breeders). The invention also relates to a method for administrating the agent near the end of a bird""s reproductive cycle to maintain and extend its reproductive productivity. All three applications of the invention result in a transient lowering of the level of a thyroid hormone and elevation of plasma gonadotropin levels.
The invention is also directed to a method of preparing the diets of the animals and their storage to ensure a uniform distribution and stability of the agent thereby effecting a uniform gonadal response by the animals consuming the rations.
The invention serves not only to bring animals earlier into the reproductive state. When coupled with photoperiodic manipulation, the agent can be withdrawn from the diet and the reproductive state can be maintained by photostimulation with a long, daily photoperiod.
In addition, the present invention overcomes the problem of early cessation of the reproductive systems of animals. In the poultry industry, some males exhibit a collapse of their reproductive system earlier than expected. The result is a significant decrease in the fertility of eggs produced by a particular flock. According to the present invention, an agent which results in reduced levels of a thyroid hormone and elevated gonadotropin blood levels can be administered to the animal to maintain or extend the length of the viable reproduction period.
The agent also stimulates gonadal development in female poultry. Thus, the invention also relates to a method for stimulating development of the ovary of female poultry, comprising administering to said poultry an effective amount of the agent. The invention also relates to a method for maintaining egg production of female poultry for a period of time longer than usual, comprising administering to said poultry an effective amount of the agent near the end of the reproductive stage of their life cycle.
A common practice in the poultry industry is to recycle birds for a second season. This involves inducing a molt which in turn causes regression of the gonads. The agent can be used to bring birds back into a reproductive state sooner. In addition, the agent can be used at the end of the second reproductive cycle to sustain their productivity for a longer period of time. Thus, in a method to recycle birds for a second season involving inducing a molt whereby regression of the gonads occurs, the invention also relates to the improvement comprising administering to the birds an effective amount of the agent, whereby the birds are brought back into a reproductive state sooner. The invention also relates to a method to sustain the reproductive productivity of recycled birds at the end of their second reproductive cycle, comprising administering to the birds an effective amount of the agent. The invention is not limited to chickens and has beneficial effects in turkeys, quail, guinea fowl, ducks, game birds and other avian species.
In addition to stimulating gonadal development, the compound likewise stimulates song in pet birds that have regressed gonads. Thus, the invention also relates to a method to stimulate song in a pet bird that has regressed gonads, comprising administering to the bird an effective amount of the agent.